In recent years, hematopoietic stem cell transplantation has been widely performed for the purpose of treating hematopoietic organ tumor, solid carcinoma, leukemia, or hypoplastic anemia. Hematopoietic stem cell transplantation is classified, according to differences in stem cell sources or a donor's selection, into bone marrow allotransplantation, peripheral blood stem cell transplantation, and cord blood stem cell transplantation between blood relatives or non-blood relatives, and bone marrow autotransplantation, peripheral blood stem cell transplantation, and cord blood stem cell transplantation performed in the donor of the transplanted cells. Of these hematopoietic stem cell transplantation techniques, bone marrow allotransplantation is a widespread method of treatment, but poses the problem of a heavy burden on the donor associated with bone marrow collection.
Recently, the clinical application of peripheral blood stem cell allotransplantation has proceeded in place of bone marrow allotransplantation imposing a heavy burden on the donor. Peripheral blood stem cell allotransplantation has advantages, such as a light burden on the donor during hematopoietic stem cell harvest, and prompt recovery of the recipient's neutrophils and thrombocytes. However, peripheral blood stem cell transplantation causes GVHD as does bone marrow transplantation, and its control has become a problem.
GVHD is a generic name for diseases due to an immune reaction which immunocompetent cells transferred or transplanted into a host causes against the tissues of the host. A major cause of GVHD is believed to be the immune response of immunocompetent cells, such as mature T cells contained in the peripheral blood transferred or transplanted, against the recipient's tissues. GVHD includes acute and chronic diseases, with clinical manifestations ranging from dermal symptoms to diarrhea and jaundice, and shows severe, sometimes lethal, response.
Methods for suppressing GVHD have been by the use of immunosuppressants such as methotrexate and cyclosporin A, and the removal of mature T cells from a transplanted cell population (graft). When methotrexate or cyclosporin A is used, side effects of such drugs on the living organism present a major problem. The side effect of cyclosporin A is strong renal toxicity, and the side effect of methotrexate is bone marrow depression.
GVHD can be suppressed by the removal of mature T cells from the transplanted cell population, but this method has been shown in that suppression of anti-tumor activity, as noticed by relapse of leukemia (see Blood, 78:2120-2123, 1991). Thus, the T cell removal therapy requires a check for ensuring the anti-tumor effect.
Various studies are under way to investigate influence on GVHD in a recipient who underwent transplantation of hematopoietic stem cells induced by the administration of granulocyte-colony stimulating factor (G-CSF) to a donor. It has been reported that when G-CSF is administered to a human, mononuclear cells or CD4−CD8−αβ+ cells increase, and these cells can suppress the proliferation potency of T cells (see Clinical Immunology, 30(6):833-838, 1998). There is also a report that when G-CSF is administered after bone marrow allotransplantation (Allo-BMT), the occurrence of acute GVHD tends to be suppressed in comparison with a group without receiving G-CSF (see Int. J. Hematol., 62:235, 1995). However, a peripheral blood stem cell population for use in transplantation, as compared with a bone marrow cell population, has a markedly low number of stem cells proportion and is also different in the properties of stem cells. Thus, the mechanism of the action of suppressing GVHD occurring after peripheral blood stem cell transplantation has been suspected to differ from that by bone marrow cell transplantation.
In the peripheral blood, the number of hematopoietic stem cells is much smaller than in the bone marrow. Thus, it is common practice to induce peripheral blood stem cells by the administration of G-CSF to the donor. It has been reported that a cell population from the donor in a G-CSF treatment group is advantageous for defense against infection or an anti-tumor activity, but a further careful analysis is desired in connection with induction and aggravation of GVHD. Particularly, the relationship between in vivo administration of G-CSF in the donor and the recipient's chronic GVHD occurring after transplantation of peripheral blood stem cells induced thereby remains insufficiently analyzed (see Hematology & Oncology 37(5):425-432, 1998).
Under these conditions, a demand has been made for the development of a method, which causes few side effects and effectively suppresses GVHD potentially occurring after peripheral blood stem cell Allotransplantation, or a drug used for this purpose.